scholarly journals Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro

Leukemia ◽  
2002 ◽  
Vol 16 (11) ◽  
pp. 2285-2291 ◽  
Author(s):  
MK Pathak ◽  
X Hu ◽  
T Yi
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Sodium Stibogluconate ◽  
Leukemia Cell Lines ◽  
Differentiation And Proliferation ◽  
Myeloid Leukemia Cell

In Vitro and In Vivo Monitoring of Valproic Acid Effects on Gene Expression Signatures in Adult Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2605-2605
Author(s):  
Lars Bullinger ◽  
Konstanze Dohner ◽  
Richard F. Schlenk ◽  
Frank G. Rucker ◽  
Jonathan R. Pollack ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Serum Levels ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. To define an VPA in vitro “response signature” we profiled gene expression in myeloid leukemia cell lines (HL-60, NB-4, HEL-1, CMK and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. In accordance with previous studies in vitro VPA treatment of myeloid cell lines induced the expression of the cyclin-dependent kinase inhibitors CDKN1A and CDKN2D coding for p21 and p19, respectively. Supervised analyses revealed many genes known to be associated with a G1 arrest. In all cell lines except for CMK we examined an up-regulation of TNFSF10 coding for TRAIL, as well as differential regulation of other genes involved in apoptosis. Furthermore, gene set enrichment analyses showed a significant down-regulation of genes involved in DNA metabolism and DNA repair. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age<60yrs) and within the AMLSG 06-04 trial for older adults (age>60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA. First results from our ongoing analysis of in vivo VPA treated samples are in accordance with our cell line experiments as e.g. we also see an induction of CDKN1A expression. However, the picture observed is less homogenous as concomitant administration of ICE, as well as other factors, like e.g. VPA serum levels, might substantially influence the in vivo VPA response. Nevertheless, our data are likely to provide new insights into the VPA effect in vivo, and this study may proof to be useful to predict AML patients likely to benefit from VPA treatment. To achieve this goal, we are currently analyzing additional samples, and we are planning to correlate gene expression findings with histone acetylation status, VPA serum levels, cytogenetic, and molecular genetic data.

MiR-34b Promoter Methylation and Regulation of CREB Expression In Myeloid Transformation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 538-538
Author(s):  
Elena Manara ◽  
Emma Baron ◽  
Alessandra Beghin ◽  
Claudia Tregnago ◽  
Emanuela Giarin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Fetal Liver ◽  
Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Myeloid Leukemia Cell

Abstract Abstract 538 The cAMP response element binding protein (CREB) is a nuclear transcription factor downstream of various stimuli and is critical for the pathogenesis of leukemia. CREB overexpression promotes abnormal proliferation, cell cycle progression, and clonogenic potential in vitro and in vivo. We found that CREB deregulation in Acute Myeloid Leukemia (AML) is due to both genomic amplification and aberrant miRNA expression. CREB has been shown to be a direct target of the microRNA, miR-34b. The inverse correlation between CREB and miR-34b expression has been described in myeloid leukemic cell lines. Mir-34b restoration reduced CREB levels and leukemia proliferation in vitro. One reason for the lower expression of miR-34b in myeloid leukemia cell lines is the hypermethylation of its promoter. Our goal was to characterize the role of miR-34b in AML progression using primary cells and mouse models. We also studied the regulation of miR-34b expression in cells from patients with AML and myelodysplastic syndromes (MDS). Primary AML cells transiently overexpressing miR-34b had decreased clonogenicity, as well as increase in apoptosis (9.9 vs. 25.5%, p<0.001). Primary leukemia cells from AML patients (n=3) treated with the demethylating agent 5-aza-2′-deoxycytidine showed a rise in miR-34b expression after 16 hours (RQ=7±2.6). We also observed a concomitant decrease in CREB protein expression and its target genes. In vivo, miR-34b overexpression resulted in decreased CREB expression and suppression of leukemia growth in flank tumor models with HL-60 and K562 cells injected into NOD-SCID IL-2receptor gamma null (NSG) mice, measured by bioluminescence and tumor volume (n=10 per group). These results demonstrated that miR-34b is an important tumor-suppressor through downregulation of CREB. We next investigated miR-34b expression in a large series of AML patients (n=118), a group of MDS patients (n= 49), and healthy bone marrows (HL-BM) (n=17) by quantitative PCR. Our results demonstrated lower miR-34b expression in blast cells from AML patients at diagnosis compared to HL-BM. The lower miR-34b expression in AML patients correlated with elevated CREB levels, similar to myeloid leukemia cell lines. The expression levels of miR-34b in bone marrow from MDS patients were intermediate between AML patients and HL-BM. These results suggest that miR-34b regulates CREB and is involved in the evolution of MDS to AML. In an effort to understand the mechanism of miR-34b downregulation in primary AML and MDS BM cells, miR-34b promoter methylation was determined using MS-PCR in both patient cohorts. The miR-34b promoter was found to be methylated in 65% (78/118) of AML patients at diagnosis, while it was unmethylated in all MDS samples (49/49). In particular, 3 MDS patients that evolved to AML had miR-34b promoter hypermethylation exclusively at the onset of AML. We further tested this hypothesis by downregulating miR-34b in primary HL-BM and fetal liver cells by using both oligonucleotides and a lentiviral transduction. An increase in CREB mRNA and several CREB target genes (for example cyclin B1, cyclin E2, p21) was observed. Moreover, the cell cycle profile demonstrated increased numbers of cells in S phase compared to negative controls. Methylcellulose colony formation was also increased in HL-BM and fetal liver cells transduced with a miR-34b inhibitor compared to controls (197 vs. 101, p<0.001). Therefore, we conclude that miR-34b promoter methylation is critical for the pathogenesis of AML through regulation of CREB-dependent pathways. Disclosures: Sakamoto: Abbott Laboratories, Inc.: Research Funding; Genentech, Inc.: Research Funding.

scholarly journals Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib

Glycobiology ◽  
2015 ◽  
Vol 26 (4) ◽  
pp. 343-352 ◽  
Author(s):  
Silvina Laura Lompardía ◽  
Mariángeles Díaz ◽  
Daniela Laura Papademetrio ◽  
Marilina Mascaró ◽  
Matías Pibuel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Chronic Myeloid Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Myeloid Leukemia Cell

KRN5500 induces apoptosis (PCD) of myeloid leukemia cell lines and patient blasts

2000 ◽  
Vol 24 (9) ◽  
pp. 741-749 ◽  
Author(s):  
Kimo C Stine ◽  
Bryce A Warren ◽  
Robert L Saylors ◽  
David L Becton
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Myeloid Leukemia Cell

scholarly journals FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells

Blood ◽  
1996 ◽  
Vol 88 (9) ◽  
pp. 3383-3390 ◽  
Author(s):  
AM Turner ◽  
NL Lin ◽  
S Issarachai ◽  
SD Lyman ◽  
VC Broudy
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Leukemia Cell ◽  
Colony Growth ◽  
Receptor Expression ◽  
Flt3 Ligand ◽  
Leukemia Cell Lines ◽  
Kit Receptor ◽  
Myeloid Leukemia Cell

FLT3 ligand is a hematopoietic growth factor that plays a key role in growth of primitive hematopoietic cells. FLT3 receptor mRNA is found in early hematopoietic progenitors and in human myeloid leukemia blasts. Much less is known about the surface expression of FLT3 receptor on human hematopoietic cells. Using human 125I-FLT3 ligand, we have identified and characterized surface FLT3 receptors on normal and malignant human hematopoietic cells and cell lines. Our results showed that surface display of FLT3 receptor was greatest in fresh myeloid leukemia blast cells and myeloid leukemia cell lines. Erythroleukemic and megakaryocytic leukemia cell lines (n = 5) bound little to no 125I-FLT3 ligand. Scatchard analysis of 125I-FLT3 ligand binding data shows that three myeloid leukemia cell lines, ML-1, AML-193, and HL-60, as well as normal human marrow mononuclear cells, exhibit high affinity FLT3 receptors. Crosslinking of 125I-FLT3 ligand to FLT3 receptors on the surface of ML-1 myeloid leukemia cells indicates that the FLT3 ligand. The rates of FLT3 ligand internalization and degradation were determined by binding 125I-FLT3 ligand to ML-1 cells and acid stripping to distinguish surface bound from internalized ligand. Internalized 125I-FLT3 ligand was detected within 5 minutes after binding to ML-1 cells. In addition, we evaluated the effect of FLT3 ligand on megakaryocytic colony growth and nuclear endoreduplication, alone or in the presence of thrombopoietin. FLT3 ligand did not promote colony forming unit megakaryocyte (CFU-Meg) colony growth or megakaryocyte nuclear maturation, nor did FLT3 ligand augment the effects of thrombopoietin on these measures of megakaryopoiesis. These data indicate that the FLT3 receptor shares several characteristics with the c-kit receptor including dimerization and rapid internalization. However, the more restricted cellular distribution of the FLT3 receptor may target the effects of FLT3 ligand to primitive hematopoietic cells and to myeloid and lymphoid progenitor cells, in contrast to the pleiotropic effects of the c-kit receptor ligand, stem cell factor.

Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in Myeloid Leukemia Cell Lines and Function in a PML and PML-RAR Independent Manner

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1497-1504 ◽  
Author(s):  
Zhu-Gang Wang ◽  
Roberta Rivi ◽  
Laurent Delva ◽  
Andrea König ◽  
David A. Scheinberg ◽  
...  
Keyword(s):  
Cell Line ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Nuclear Bodies ◽  
Independent Manner ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Abstract Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has been proposed to principally target PML and PML-RAR proteins in APL cells. We investigated the activity of As2O3 and melarsoprol in a broader context encompassing various myeloid leukemia cell lines, including the APL cell line NB4-306 (a retinoic acid–resistant cell line derived from NB4 that no longer expresses the intact PML-RAR fusion protein), HL60, KG-1, and the myelomonocytic cell line U937. To examine the role of PML in mediating arsenical activity, we also tested these agents using murine embryonic fibroblasts (MEFs) and bone marrow (BM) progenitors in which the PML gene had been inactivated by homologous recombination. Unexpectedly, we found that both compounds inhibited cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10−7 to 10−5 mol/L. As2O3 relocalized PML and PML-RAR onto nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60 and U937 cell lines. Although melarsoprol was more potent in inhibiting growth and inducing apoptosis, it did not affect PML and/or PML-RAR nuclear localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth and induced apoptosis of PML+/+ and PML−/− MEFs, and inhibited colony-forming unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of PML+/+ and PML−/− progenitors. Together, these results show that As2O3 and melarsoprol inhibit growth and induce apoptosis independent of both PML and PML-RAR expression in a variety of myeloid leukemia cell lines, and suggest that these agents may be more broadly used for treatment of leukemias other than APL. © 1998 by The American Society of Hematology.

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